Alleviating the Effects of Short QT Syndrome Type 3 by Allele-Specific Suppression of the KCNJ2 Mutant Allele.

Short QT syndrome type 3 (SQTS3 or SQT3), which is associated with life-threatening cardiac arrhythmias, is caused by heterozygous gain-of-function mutations in the KCNJ2 gene. This gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac inward rectifier potassium current (IK1). These gain-of-function mutations either increase the amplitude of IK1 or attenuate its rectification. The aim of the present in silico study is to test to which extent allele-specific suppression of the KCNJ2 mutant allele can alleviate the effects of SQT3, as recently demonstrated in in vitro studies on specific heterozygous mutations associated with long QT syndrome type 1 and 2 and short QT syndrome type 1. To this end, simulations were carried out with the two most recent comprehensive models of a single human ventricular cardiomyocyte. These simulations showed that suppression of the mutant allele can, at least partially, counteract the effects of the mutation on IK1 and restore the action potential duration for each of the four SQT3 mutations that are known by now. We conclude that allele-specific suppression of the KCNJ2 mutant allele is a promising technique in the treatment of SQT3 that should be evaluated in in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]